Gout Uric Acid
I’d like to add gout as another area that Dr. Kats can give us advice on. Gout causes problems for a... View more
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Gout: Try, Try Again
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Gout: Try, Try Again
I am 6 weeks into a two-footed gout attack, worst by far of my life and only the second in the last five years. At the onset, I was moving up to 5 grams Niacin with (the then current) Lactoferrin and Folic acid protocol. A few days after the attack began, my Pure Bulk Glutamine arrived and I immediately switched over. Pain and swelling were so severe I couldn’t walk and stayed off my feet all day, losing strength in my legs and feet but no choice. Somewhere in those 6 weeks I stopped using the protocol altogether. All the usual internet “home remedies” failed me but at least didn’t worsen the condition. The only thing I tried with some success was 2 grams/day of potassium. This is no way to live.
I signed up today to get me back on track. One and only goal is a complete reversal of gout.
Pure Bulk N and Pure Bulk Glutamine. I’ve used Zephyr Hills spring water in the past, will switch over to distilled. I’m starting with 500 mg N and 600 mg G once per day. I will do this for probably 3 days, then creep upward. If there’s a better approach, I haven”t found it on this board yet. Solutions welcome.
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11 Replies
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This is FAR too little of dose… the 5 g you were hitting of flush niacin with candidate cofactors with it, not glutamine, should be retained with glutamine … 6 g doses, for instance, of glutamine (with 5 g niacin) to get therapy going is not atypical.
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With all due respect, before you determined the 1/1.2 ratio of N/G, you told me via Telegram group to go 10 g N/30 g G. It made the flare up worse. So I’m not emotionally ready to go 5N/6G yet.
Is this approach supposed to lower my Uric acid, increase uric excretion or work by some other pathway? Not being obstinate but I’d appreciate further researched assurance before risking another flare up. The last one cost me six weeks of my life.
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Okay, so let me give you the breakdown of how the original 3:1 Glutamine:Flush Niacin mass ratio was conceived, and how it was quickly changed:
Per sub-Figure D below, from the following paper:
Glutamine-dependent NAD+ Synthetase: HOW A TWO-DOMAIN, THREE-SUBSTRATE ENZYME AVOIDS WASTE
https://www.jbc.org/article/S0021-9258(20)70523-5/fulltext
…Intuitively, after examining the results of this study, particularly sub-Figure D (picture attached below), it would be conceivable that the whole key would simply be to meet & continue meeting at least the minimum concentration of ~125 mM glutamine in every cell dynamically forward (sub-Figure D), corresponding to niacin at at least pharmacological doses to continue to make at least 600 uM NaAD+ intracellularly, which equates to accordingly, 600 uM flush niacin, given 1 niacin makes 1 NaAD+ (so 1:1 mole of niacin:NaAD+). Dividing glutamine’s then 125 mM concentration by (1 mole niacin to make 1 mole NAaD+,
so 1 *) 600 uM for that of niacin’s, gives a respective 2.5 (glutamine) to 1 (niacin) as the molar ratio of niacin to glutamine, in turn explaining the originally devised mass ratio of glutamine to niacin as 3 to 1.Variability of glutamine concentration across the body’s cells (coming into this co-supplementation upon now realizing diet’s deficiencies and what that led to over life to this point) ranges from completely void to some measurable degree of lacking of at least that 125 mM depicted in sub-Figure D needed to be met (& maintained) to continue to efficiently.
Further, to most efficiently catalyze niacin’s de novo NAD+ biosynthesis (& everything beyond that then follows), all exogenous glutamine will be maximally converted to glutamate, assuming glutamine + niacin are dosed at adequately high-enough and at equimolar amounts, as this is what is depicted per this wonderful paper as the fashion in which flush niacin + glutamine enter each cell through the body in fact (see second pic below from this article):
A New Step in the Treatment of Sickle Cell Diseasehttps://pubs.acs.org/doi/10.1021/acs.biochem.7b00785
…
to have to be most favorable to occur then to assume this quaternary complex (depicted in second pic attached below) forward with niacin’s NAaD+ catalyzed by equimolar glutamine. Meanwhile, providing sufficient equimolar amounts of the two, in turn, to fuel NAD+ biosynthesis and beyond, will also be accomplished w/o any NH3 (ammonia) waste, assuming enough niacin is dosed to lead to cellular concentrations of 600 uM NAaD+.Moving forward, this glutamate that is formed with sufficient + equimolar glutamine + niacin doses, becomes optimally powered to proceed thereafter to glutathione and to the citric acid and beyond, powered by flush niacin going to NAD+ (and redox.. & beyond), to ultimately make ATP, by way of the restoration of (above paper’s noted) NAD+/NADH/NADPH/NADP+ redox along with NAADP+/autophagy/T-cells/clearance of particles, as well as ultimately, the electrochemical balance. Moreover, for the first time, this will finally allow the NAD+ biosynthesis, fueled by sufficient amounts of the two in equimolar ratio as depicted, to power-glide all conversions of glutamine & intermediates forward, likely even—with enough dosing met—all the way around the citric acid cycle, synergized by well-balanced diet and enough clean (ideally distilled, not above room temp. water).
The quickly updated to now correct stoichiometric 1:1 molar ratio corresponds to a mass ratio of 1:1.187, i.e., 1 molecule of flush niacin to makes a corresponding 1 NaAD molecule (and is moiety of NaAD), which complexes with each 1 glutamine molecule in reaction, and so dividing glutamine’s molar masses by that of niacin’s, gets 1.187 times (in mass) as much glutamine as niacin in grams.
^ Hence, the previous 1:3 flush niacin:glutamine mass ratio was (3 divided by 1.187 =) 2.527 times greater glutamine (in mass) dose coming each time with flush niacin. This excess glutamine coming in (2.527x as much needed each time) with niacin, led to acute arousal of symptoms by way of then not having that needed niacin with it to turn to NAD+ & beyond, and instead staying as glutamate and into glutamic acid out the cell, further depleting purines/DNA synthesis, and in this way, not being able to make glutamate properly to fuel purines synthesis without equimolar niacin alongside (as per the following recently published paper):
“We demonstrated that fructose promoted purine de novo synthesis to generate IMP and drive conversion of IMP to AMP to maintain the rapid depletion of ATP. Fructose increased the breakdown of preformed PNs and their derivatives (adenine, xanthine, and hypoxanthine), accelerated their degradation to UA [uric acid], and increased the serum UA level. This work revealed that increased purine de novo synthesis may be a crucial mechanism in fructose-induced hyperuricemia.
Conclusion: This study demonstrated that the increased purine de novo synthesis may be a crucial mechanism for fructose-induced hyperuricemia.”
Dietary intake of fructose increases purine de novo synthesis: A crucial mechanism for hyperuricemia
https://www.frontiersin.org/articles/10.3389/fnut.2022.1045805/full
…Now, check out this seminal paper (which note also how they used garbage extended/sustained release formulation of niacin, and not flush niacin (immediate release nicotinic acid), despite these curative effects reported for a similar process:
Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30190-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS155041312030190X%3Fshowall%3Dtrue…
Specifically glancing at Figure 5E (third pic attached below), we see how the lack of substrates/reactants to continue to achieve homeostatic purine synthesis is induced & augmented upon & over, respectively, the niacin deficiency (and ultimately, with niacin’s deficiency, we then learned, with glutamine’s alongside it; but as explained here, glutamine depleting alongside with flush niacin in a 1:1.187 & not originally conceived 1:3 mass ratio).Among many other key components, (albeit not folate or even flush niacin itself, given we need glutamine alongside), niacin restored IMP (even solo, underpowered without compensatory equimolar (i.e., 1.187x as much as niacin,) glutamine, and as the inferior, hepatotoxic, while also glycemic control-incapable sustained/extended release formulation):
(E) One-carbon metabolism and associated pathways in patient muscle pre- and post 10-month niacin. Colored text, changed at baseline; red, increase; green, decrease. Circled metabolites, changed upon niacin; red, increase; green, decrease. SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; IMP, inosine monophosphate; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; GAA, guanidino-acetic acid; MTA, 5′methylthioadenosine; ROS, reactive oxygen species; THF, tetrahydrofolate, MTHFD, methylene-tetrahydrofolate dehydrogenase; dTMP, deoxythymidine monophosphate.“Niacin and NAM metabolism was among the most significantly changed pathways, as a proof of principle, as were the biosynthetic pathways for purine, pyrimidine, methionine, and glycine metabolism, and bile acid and protein biosynthesis (Figure 5B). PEO patient muscle has imbalanced nucleotide precursor amounts (Nikkanen et al., 2016), of which inosine monophosphate and adenosine of purine synthesis were brought back to control level by niacin treatment (Figures 5C and 5E).”
The high uric acid-related flare-ups of gout are stimulated by not only, prominently, fructose (when you are this (equimolar) niacin + glutamine deficient), but really anything that can bring them on by way of, for instance, fructose having to generate IMP to fuel its breakdown to fuel the extra ATP needed now in compensation for the decreasing availability of niacin + glutamine for (among so many other goodies, proper) purine synthesis over the growing properly addressed deficit of equimolar niacin + glutamine. Fructose and other compounds have to be sacrificed in this fashion to continue to fuel this needed ATP by way of fueling the synthesis into breakdown of purines to do this in order to try to achieve this ATP demand. In severely niacin + glutamine deficient conditions, we accumulate uric acid as less allanotin continues to be made (again, please refer to the third pic attached, Figure 5E) and hypoxanthine can’t be fueled by niacin’s NAD+ to make xanthine or uric acid to turn to it this way too. The participants in this trial were not that glutamine deficient (and thus also niacin in equimolar amount) as you (/individuals living with recurring gout) are, and so even intermittently-released “niacin” was able to cure their systematic mitochondrial myopathy, albeit after a year. They were borderline completely folate deficient at baseline, in fact, but still enough, thus glutamine too, to fuel “niacin” to curative effects demonstrated after a year of low (b/c the SR/ER “niacin” is hepatotoxic at high doses, unlike flush niacin, as we know) dosing.
As the purine synthesis and its metabolism–ultimately the energy metabolism–restore by way of properly (i.e., 1:1.187 mass ratio + via sufficient levels of dosing) addressing the causative agents’, flush niacin + glutamine’s, deficiencies together, these flare-ups and the entire condition disappears. We know we have a lot to make up to achieve this, but it is totally understandable to be wary now and build up with dosing. I completely get it.
With sufficient (whatever it is, but we expect to need a lot these days, especially with nagging gout) and exactly equimolar glutamine matched with flush niacin alongside, exogenous glutamine will react nowhere else first but with then flush niacin’s NaAD+ through the formation of the quaternary complex (second pic attached below), as uniting with niacin’s NaAD+ into and only by way of this arrangement, constitutes the most thermodynamically favorable (and ONLY) route for the system/body/host/human (for example) to recover. The lack into deprivation of these two into now not to a T addressing the need for flush niacin + glutamine to be restored sufficiently but in equimolar (1:1.187 mass ratio) amounts is how this happened in the first, second, third, … and now, Nth place.
Single doses of at least 5 g flush niacin + 5.935 g glutamine will be expected — maybe up to even double that at least once a day (with in complement, a lower dose earlier &/or later that day, or even wait 18-36 h for the next dose if you see you are needing these higher levels earlier, and so likely they need some extra time to fully process/metabolize through to prep the body ideally for the next one) — for a week to really get things going. This is again the exact same mechanism I was trying to express earlier, but did not have these intricacies ironed out just yet, I apologize) are to be expected again, but this time, they will NOT be coming with that extra 9.065 g of glutamine excess this time (as you did with a 5 g flush niacin + 15 g glutamine dose before per the incorrect 1:3 mass ratio initially conceived).
I am very eager to hear how the updated, correct 1:1.187 (equimolar) mass ratio of the two goes from whatever dose amount. I am just letting you know that the dose to really overpower this, mechanistically speaking, is going to need to hit these needed (relatively higher) levels. Please build up to comfort. It will be a very good sign if the low dosing where you are starting do not lead to any flare-ups, or they dissipate as you go forward/up with dosing. This is what I expect. Please keep me updated. Do not worry.
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Sincere thanks to you for taking all the time to respond to my concerns. I truly appreciate the depth of your dedication here.
I decided to give the N/G protocol a fredh start tomorrow as 1) I haven’t yet gotten distilled water and 2) I was going to using my feet very much today and, if they ended the day tired/ sore/swollen (which they didn’t) N/G couldn’t be the cause.
I will update as things develop.
As a final note in my own research I was narrowing in on fructose as a primary cause of either over production or under excretion of UA. Your posted research supports this too.
I wonder why so little mention is made of insulin’s role in gout as the symptoms of gout and hyper insulin are so similar. Is there a connection?
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“Elevated insulin inhibits uric acid clearance and excretion. This observation has been made in healthy people and in those with hypertension. The kidneys are especially sensitive to insulin—something easily demonstrated by the effect of insulin on blood pressure: the ‘anti-natriuresis’ action (inhibition of sodium excretion) partly accounts for the role of hyperinsulinemia in hypertension. Elevated insulin increases retention of uric acid as well as sodium.”
Effect of insulin on uric acid excretion in humans
https://sci-hub.ru/https://doi.org/10.1152/ajpendo.1995.268.1.E1…
“Interestingly, evidence suggests higher protein intakes are not associated with increased risk for gout. A paper in The New England Journal of Medicine [see below link] noted that high-protein diets are associated with increased excretion of uric acid and may reduce blood uric acid level. One small study in Caucasian men with gout showed that a proportional increase in protein intake to 30% of calories (along with other dietary changes such as reduced carb intake [to 40% of calories] and emphasis on unsaturated fats) led to a significant reduction in serum uric acid and rate of gout attacks.”
Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men
https://www.nejm.org/doi/full/10.1056/nejmoa035700… ^ but this is NOT high-protein / Atkins diet, rather, efficiently with glutamine (+ niacin) …
“In a small study of overweight or obese subjects, a high-protein diet—actually referred to by name as the Atkins diet—resulted in dramatic decreases in fasting insulin (cut nearly in half) along with lower UA levels, with those with the highest UA concentration experiencing the greatest decrease. Additionally, triglycerides fell by nearly 25% and HDL-cholesterol increased slightly, all indicative of improved insulin sensitivity. The study’s conclusion was clear: ‘Our findings suggest that the Atkins diet (i.e., a high protein diet without calorie restriction) can reduce SUA levels despite substantial purine loading.’
So it seems that increased dietary protein intake may actually be beneficial for individuals with gout—provided that carbohydrate intake is reduced. In noting that dietary advice for people with gout typically calls for limiting protein and encouraging ‘the unlimited use of several food substances high in carbohydrate,’ the authors of a study cited above concluded, ‘Current dietary recommendations for gout may need re-evaluation.’
The underlying pathology of elevated insulin in gout is echoed by findings that serum uric acid levels positively correlate with erectile dysfunction, which in some men may come from chronic hyperinsulinemia. Women with PCOS have been shown to have higher uric acid levels compared to controls as well, even after adjusting for BMI. It’s time to recognize that modern dietary patterns are contributing to gout, but not in the way we once may have thought.”
High-Protein Diet (Atkins Diet) and Uric Acid Response
https://acrabstracts.org/abstract/high-protein-diet-atkins-diet-and-uric-acid-response/…
Gout and Diet: A Comprehensive Review of Mechanisms and Management
https://www.mdpi.com/2072-6643/14/17/3525/pdf…
“Consumption of animal protein and seafood had been linked with elevated hyperuricaemia prevalence, whereas soy product consumption was related with decreased hyperuricaemia prevalence among middle-aged Chinese men [35]. Uric acid concentrations accelerated following fructose-rich food intake, that triggers uric acid formation by accelerating ATP degradation to AMP, a urate precursor [36] including an enormous quantity of purine intake [37]. Purine-rich food consumption is connected with both the incident and acute gout events.”
Functionalities of Purines in Health and Disease
https://zenodo.org/record/2548176
…Role of NifS in maturation of glutamine phosphoribosylpyrophosphate amidotransferase
https://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=943D2DFF329EC422D98A92C646C95CB2?doi=10.1.1.612.6102&rep=rep1&type=pdf…
“These results indicate that the urea and TCA cycles as well as amino acid metabolism were highly activated in the RA group compared with the non-RA group consisting of AS, BD, and gout patients. In addition to citrulline, succinate, asparagine, [low] glutamine, and lysine can be considered as major biomarkers for RA diagnosis.”
Global Metabolite Profiling of Synovial Fluid for the Specific Diagnosis of Rheumatoid Arthritis from Other Inflammatory Arthritis
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097501So basically gout = pretty prolonged unaddressed flush niacin + glutamine deficiency, with some diet items then leading to outbreaks erratically given these deficiencies.
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Your posts above are spot on* and I thank you for them.
My amateurish research kept showing a connection between hyperglycemia/IR and gout. You are digging this out. And I’ve experienced some of this – there can be a log of up to 24-36 hours from the time I eat a higher carb/high glycemic meal and when I get either a tightness in my foot/feet or even a swollen lip/fingertip/tongue. I have now come to believe that these occasional swellings I get are a canary in the coal mine to forewarn me that my UA is getting dangerously high. Right now I have a slightly swollen lower lip from a meal I ate Sunday noon.
Interesting that you posted a day or two ago of the dangers of the ketogenic diet and then today positive outcomes on the Atkins diet. I am operating on the assumption that, until this metabolic crap inside of me is re-regulated by N-G protocol, that it would be best to limit added sugars and hyperglycemic foods of all sorts. No grains/sugars/alcohol/processed foods. Losing 15 pounds would hurt either.
Yesterday’s dose was 4/4.748. Considering the swollen lip I have today, I will repeat that today and not increase.
*as you already know!
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Quick update
I’ve moved up to 6/7.2 twice a day. Swelling is 100% gone in my right foot, 90+% in the left. No pain. Left foot has a small knob (nob?) at the big toe joint, right has a really small one but both seem to be down from their peak size.
Despite what it says on Mayo Clinic’s website, niacin is not causing a build up of uric acid, even at the 12 g total per day level. Sorry, Mayo, but Dr. K is doing the research that you should be doing.
I continue to limit the big three kidney killers: fructose/alcohol/hyperglycemic foods. I confess that I took my wife out to dinner last night to celebrate our anniversary and I split a dessert with her. No repercussions.
My biggest concern is for upcoming travel. I’m bringing a supply of N and G capsule (Pure Bulk and Pure Encapsulations respectively) and will go on more of a maintenance dose for 9 days. Maybe like 2.5/3 per day.
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Yes, a lot of these disorders just take a lot of overpowering with the niacin and glutamine… this is great to hear things are subsiding .. and yes, you will not have to do as high of dosing consistently as before as it fully goes away … and yes, for travel, what I would also do is get the bovine gelatin capsules for on the go (if you do check-in luggage, you could bring the powders and scale and everything)
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Upped dosage today to 2X 8/9.6. The first dose after breakfast was smooth, almost no flush. The second, about five hours later after lunch, however, caused upset stomach/loose bowels. I suppose that’s a sign to level off a bit.
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Hmmm – what did you eat for lunch? And how did you prepare the doses? It may be better for some people early-on pre-meals…
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Same lunch as the day before. Some chicken, mozzarella slices/tomato/basil.
No matter. I backed off to a total of 10/12 yesterday and everything was fine. For the next 10 days it’ll be 2.5/3 as I travel.
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